In this study, we examine the synergistic modulation of NHRs Nr2e3 and Rora, miRNAs, and the epigenetic factor Ezh2. As both NR2E3 and RORA have been implicated in AMD, we evaluated our miRNA potential gene targets as well as differentially expressed genes from each mouse model against gene expression data from a large cohort of AMD patients’ donor eyes from unrelated subjects. Here, EZH2 is linked to age-related macular degeneration.